Most patients who die from cancer do so because their cancer is resistant to available therapies. Tumors are comprised of diverse multicellular ecosystem that include malignant and non-malignant cells. Changes in the cellular state, spatial organization and interaction between subsets of cells in that ecosystem are likely to be central to cancer progression and therapeutic resistance, but invisible by bulk analyses. Thus, there is urgent need to chart an atlas of the cells that compose a tumor, their spatial organization and functional relationships and how those features differ in tumors that are resistant to therapy. The Boston Human Tumor Atlas Network Research Center (HTA-RC) will create three comprehensive atlases of the cellular geography of human cancer to understand how changes in the tumor ecosystem lead to therapeutic resistance. The atlases will chart the dynamic changes associated with resistance to targeted and immune-based therapies in: (1) Primary and acquired resistance to CDK4/6 inhibition in breast cancer; (2) Primary and acquired resistance to immune checkpoint blockade in metastatic melanoma; and (3) Primary resistance to immunotherapy in microsatellite stable (MSS) colorectal carcinoma (CRC) compared with microsatellite instable (MSI) CRC. To enable these goals, the Biospecimens Unit (BSU) will provide a comprehensive, rigorous, and nimble sample acquisition platform that provides the bridge between the clinic and a set of state-of-the-art cellular and spatial analytic assays that will form data backbone for the atlases. It will provide at least 100 clinically and pathologically annotated samples/year to the Molecular Characterization Unit (MCU) in a manner adequate for three downstream measurement modalities: (1) histopathology, based on H&E stains and pathology reports; (2) spatial multiplex RNA and protein data (by MERFISH, IHC, CODEX, and MIBI); and (3) single-cell genomics data, especially single cell and single nucleus RNA-Seq (scRNA-seq, snRNA-Seq). The proposed studies build on an established, tight local collaboration network that has already proven as a highly effective pioneer in generation of pilot-scale tumor atlas datasets. expand this infrastructure and the extensive experience within our clinical units to assure its success in the following aims: Aim 1: Collect biospecimens from resections and biopsies of breast cancer, melanoma and colorectal carcinoma. The BSU will identify, procure, and traffic samples from surgical suite to the laboratory. Aim 2: Conduct pre-analytic processing of biospecimens: The BSU will perform pre-analysic processing steps of biospecimens including tissue dissociation, snap freezing, sectioning for spatial analysis and archiving. Rigorous SOPs and quality control measures for each step already well-developed and employed routinely. Aim 3: Acquire and maintain clinical data associated with each sample: Accurate and comprehensive clinical pathological annotation will be linked to each sample, including careful assessment of the patients' outcomes.